| The Conditions for Initiating "All-or-Nothing" Repolarization in Cardiac Muscle Biophysical Journal, Volume 3, Issue 4, 1 July 1963, Pages 261-274 D. Noble and A.E. Hall Abstract Solutions have been computed for the point polarization of an infinite cable-like membrane obeying the equations used to reproduce the Purkinje fiber action potential (Noble, 1960, 1962) in order to determine the conditions for initiating all-or-nothing repolarization during the action potential plateau. It was found that all-or-nothing repolarization would not be obtainable during the first half of the action potential in spite of the fact that the membrane current-voltage relations contain regions of negative conductance. At the point at which the all-or-nothing response is first obtained, the computed threshold is large and repolarization almost back to the resting potential would be required in order to initiate the response. The results are discussed in relation to the experimental evidence at present available on repolarization in heart muscle. Abstract | PDF (951 kb) |
| Genetic modifiers of cardiac arrhythmias Trends in Molecular Medicine, Volume 9, Issue 2, 1 February 2003, Pages 59-66 Ching-Feng Cheng, Hai-Chien Kuo and Kenneth R Chien Abstract Rhythmic contraction of a four-chambered mammalian heart is a highly coordinated process, requiring a functional conduction system. Both acquired and inherited forms of arrhythmia can be life threatening, and are major causes of mortality and morbidity in developed nations. Knowledge derived from human genetics and from studies of mouse genetic models has led to the discovery of multiple molecular defects responsible for arrhythmogenesis, including mutations in ion channels, cytoplasmic ion-channel-interacting proteins, gap-junction proteins, transcription factors and, most recently, a kinase subunit. However, phenotypic expression of a given mutation does not always appear to be uniform in human patients, implying a contribution from environmental factors and/or the presence of other genetic modifiers. Accumulating evidence suggests that ‘multiple hits’ affecting the interaction and integrity of multiple pathways might be responsible for many forms of arrhythmia. Abstract | Full Text | PDF (481 kb) |
| Ionic Determinants of Functional Reentry in a 2-D Model of Human Atrial Cells During Simulated Chronic Atrial Fibrillation Biophysical Journal, Volume 88, Issue 6, 1 June 2005, Pages 3806-3821 Sandeep V. Pandit, Omer Berenfeld, Justus M.B. Anumonwo, Roman M. Zaritski, James Kneller, Stanley Nattel and José Jalife Abstract Recent studies suggest that atrial fibrillation (AF) is maintained by fibrillatory conduction emanating from a small number of high-frequency reentrant sources (rotors). Our goal was to study the ionic correlates of a rotor during simulated chronic AF conditions. We utilized a two-dimensional (2-D), homogeneous, isotropic sheet (5×5cm) of human atrial cells to create a chronic AF substrate, which was able to sustain a stable rotor (dominant frequency ∼5.7Hz, rosette-like tip meander ∼2.6cm). Doubling the magnitude of the inward rectifier K current () increased rotor frequency (∼8.4Hz), and reduced tip meander (∼1.7cm). This rotor stabilization was due to a shortening of the action potential duration and an enhanced cardiac excitability. The latter was caused by a hyperpolarization of the diastolic membrane potential, which increased the availability of the Na current (). The rotor was terminated by reducing the maximum conductance (by 90%) of the atrial-specific ultrarapid delayed rectifier K current (), or the transient outward K current (), but not the fast or slow delayed rectifier K currents (/). Importantly, blockade of / prolonged the atrial action potential at the plateau, but not at the terminal phase of repolarization, which led to random tip meander and wavebreak, resulting in rotor termination. Altering the rectification profile of also slowed down or abolished reentrant activity. In combination, these simulation results provide novel insights into the ionic bases of a sustained rotor in a 2-D chronic AF substrate. Abstract | Full Text | PDF (714 kb) |
Copyright © 1998 The Biophysical Society. All rights reserved.
Biophysical Journal, Volume 74, Issue 6, 2850-2861, 1 June 1998
doi:10.1016/S0006-3495(98)77992-5
Alain Pumir*,
,
, Georges Romey# and Valentin Krinsky*
* Institut Non Linéaire de Nice, 06560 Valbonne, France
# Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France
Address reprint requests to Dr. Alain Pumir, Institut Non-Lineaire de Nice, 1361 Route des Lucioles, Sophia-Antipolis, F-06560 Valbonne, France. Tel.: 33-4-92-96-73-44; Fax: 33-4-93-65-25-17.Excitation and deexcitation are fundamental phenomena in the electrophysiology of excitable cells. Both of them can be induced by stimulating a cell with intracellularly injected currents. With extracellular stimulation, deexcitation was never observed; only cell excitation was found. Why? A generic model with two variables (FitzHugh) predicts that an extracellular stimulus can both excite the cell and terminate the action potential (AP). Our experiments with single mouse myocytes have shown that short (2–5ms) extracellular pulses never terminated the AP. This result agrees with our numerical experiments with the Beeler-Reuter model. To analyze the problem, we exploit the separation of time scales to derive simplified models with fewer equations. Our analysis has shown that the very specific form of the current-voltage (I-V) characteristics of the time-independent potassium current (almost no dependence on voltage for positive membrane potentials) is responsible here. When the shape of the I-V characteristics of potassium currents was modified to resemble that in ischemic tissues, or when the external potassium concentration (K0) is increased, the AP was terminated by extracellular pulses. These results may be important for understanding the mechanisms of defibrillation.